5-Azacytidine (also called as azacytidine or by the product name of Vidaza®) and 2′-deoxy-5-azacytidine (also called as decitabine or by the product name of Dacogen®) have following chemical structures, respectively. They are collectively referred to as “azacytidines or 5-azacytidines” in this specification. It has been known that these azacytidines inhibit protein synthesis and some enzymes by incorporating into RNA or DNA during nucleic acid bio-synthesis in frequently dividing cells, and show cytotoxicity (patent documents 1-2 and non patent document 1).

In the field of anti-oncogene promoter, when incorporating into DNA in cells, the azacytidines combine irreversibly with transferase of DNA methyl group relating to 5-methylation of the cytosine ring in highly risky myelodysplastic syndrome, in which the formation of a large amount of 5-methylated cytosine moiety has been confirmed, and cause enzyme inhibition. As a result, they promote the reactivation of anti-oncogenes and accordingly have been clinically used as therapeutic agents (5-azacytidine or 2′-deoxy-5-azacytidine) showing remarkable effects on highly risky myelodysplastic syndrome (non patent documents 2-3).
However, each of these azacytidines can be easily inactivated by cytidine deaminase, a metabolic hydrolyzing enzyme in blood and liver (less than 30 minutes of half-life, non patent document 4). As the current clinical situation, they can hardly be used effectively as therapeutic agents for patients with highly risky myelodysplastic syndrome. Accordingly, countermeasures are highly demanded.
On the other hand, silyl etherification of hydroxy groups can be expected to decrease boiling points of compounds and is applied in the field of analytical chemistry as a pretreatment method of samples for gas chromatography (particularly in case of trimethyl silyl etherification in hydroxy moiety, for example, non patent document 5 and the like). Besides, it can also be used in organic synthetic chemistry as a simple protective method for hydroxy group, since de-silylation is possible in mild conditions (non patent documents 6-11).
The following examples can be given as application of silyl etherification of hydroxy group. For the purpose of selective introduction of acyl group to 4-amino group of 5-azacytidine, firstly, all of the hydroxy groups in carbohydrate moiety are trimethyl silyl etherified by trimethyl silyl chloride in the presence of triethyl amine or pyridine and the like. Then, 4-amino group is acylated by carboxylic acid anhydride or acid chloride. After that, the protective group of trimethyl silyl in carbohydrate moiety is treated with methanol containing acetic acid or alcohol (non patent documents 12-13).
In addition, examples of investigation on silyl etherification of hydroxy group in search for prodrugs of pharmaceuticals can be given as follows. Pharmaceuticals can be released under acidic physiological conditions by crosslinkage at dialkyl silyl group between organic polymers having hydroxy groups on surface and pharmaceuticals, such as camptothecin, dasatinib, gemcitabine, and the like which have hydroxy groups in their molecules. It has been shown that they can possibly be used as DDS (drug delivery system) products (non patent document 14). Moreover, it is disclosed that docetaxel, an antitumor agent, can be used as a DDS product, in which docetaxel is released under acidic physiological conditions by becoming nanoparticles according to alkyl silyl etherification at 2′-hydroxy group of docetaxel (non patent document 15).
However, there are no investigational examples of silyl etherification in carbohydrate moiety in search for prodrugs of 5-azacytidine. Furthermore, there are no examples showing that cytidines become stable against cytidine deaminase, a metabolic hydrolyzing enzyme by silyl etherification of hydroxy group in carbohydrate moiety.
Regarding silyl etherification of hydroxy group in carbohydrate moiety of cytidines, various alkyl silyl etherifications of hydroxy group in carbohydrate moiety of Ara-C or gemcitabine have been reported. However, the stability and reactivity of these derivatives have not been disclosed and there are no examples of detailed disclosure about their use as chemotherapeutic agents (patent documents 3-4).